Role of DAP12 receptors in NK cells
Natural killer (NK) cells is an important component of large granular lymphocyte
population. NK cells mediate cytolytic activity against virally infected cells and
malignant cells. [1].
The map shows signaling pathways from the activated receptors in NK cells via TYRO
protein tyrosine kinase binding protein (DAP12) [2] and inhibitory receptors. The receptors include Natural cytotoxicity triggering
receptor 2 (NKp44), Killer cell lectin-like receptor
subfamily A, member 1 (KLRA1), Killer cell
immunoglobulin-like receptor, two domains, short cytoplasmic tail, 1 and 2
(KIR2DS1, KIR2DS2), Killer cell lectin-like receptor
subfamily C, member 3 (KLRC3) and Killer cell lectin-like
receptor subfamily C, member 2 (NKG2C).
No natural ligands are known for KLRA1,
KLRC3, KIR2DS1 and KIR2DS2
[3], [4]. NKG2C, a
member of NKG2 receptor family recognizes non-conventional MHC class IB ligands: major
histocompatibility complex, class I, E (HLA-E)
[3]. Upon ligand-receptor recognition, DAP12
is phosphorylated by Lymphocyte-specific protein tyrosine kinase
(Lck) and FYN oncogene related to SRC, FGR and YES
(Fyn) [5]. These phosphorylation events result
in recruitment of SYK family kinases such as Spleen tyrosine kinase
(Syk) and Zeta-chain associated
protein kinase 70kDa (ZAP70) [6], [7], [8].
Signal transduction proceeds from ZAP70 via Linker for
activation of T cells (LAT) to the reorganization of
cytoskeletal proteins. LAT activates Phospholipase C, gamma
1 and 2 (PLC-gamma 2 and PLC-gamma 1)
[9], [10], which catalyze Diacylglycerol
(DAG) synthesis. DAG activates
Protein kinase C, theta (PKC-theta)
[11], [12]. PKC-theta
phosphorylates Wiskott-Aldrich syndrome protein interacting protein
(WaspIP). Separation of WaspIP
from Wiskott-Aldrich syndrome (eczema-thrombocytopenia)
(WASP) and activation of WASP
results in rearrangement of Actin cytoskeletal
through Apr2/3 complex.
Actin
cytoskeletal rearrangement is probably
required for cytolysis of target cells [13]. V-crk sarcoma virus CT10
oncogene homolog (avian)-like (CrkL) participates in
recruitment of WaspIP/ WASP to
Actin
cytoskeletal [11], [14].
DAP12 probably activates SHC (Src homology 2 domain
containing) transforming protein 1
(Shc) via ZAP70.
Shc binds and stimulates Growth factor receptor-bound
protein 2 (GRB2). In turn, GRB2
activates another guanine nucleotide exchange factors Son of sevenless homolog
(SOS), which transmit signal
via v-Ha-ras Harvey rat sarcoma viral oncogene homolog (H-Ras)
/ v-raf-1 murine leukemia viral oncogene homolog 1
(c-Raf-1)/ MEKs/ ERKs cascade {PMID:
16109839}.
Syk interacts with Phosphoinositide 3-kinase
(PI3K) [15] and Syk/ PI3K cascade activates Vav 2 and 3 guanine nucleotide
exchange factors (VAV2 and
VAV3) [15]. VAVs participate in
activation of mitogen-activated protein kinases 3 and 1
(ERK1 and ERK2, accordingly)
via Ras-related C3 botulinum toxin substrate 1 (RAC1)/
p21/Cdc42/Rac1-activated kinase 1 (PAK1)/
Mitogen-activated protein kinase kinase 1
(MEK1(MAP2K1)) pathway [8], [16], [17]. ERK1/2 activation results in mobilization
of lytic granules with perforin and granzyme B.
DAP12-activating receptors action in NK cells is
repressed by inhibitory receptors whch include cell immunoglobulin-like receptor, three
domains, long cytoplasmic tail, 2 (KIR3DL2) and 1
(KIR3DL1) correspondingly; Killer cell lectin-like receptor
subfamily C, member 1 (NKG2A); Killer cell
immunoglobulin-like receptor, two domains, long cytoplasmic tail 1-5
(KIR2DL1, KIR2DL2,
KIR2DL3, KIR2DL4, KIR2DL5) [1], [18], [19]
Most inhibitory receptors belong to the killer immunoglobulin (Ig)-like receptor (KIR)
superfamily which recognizes classical MHC class I molecules major histocompatibility
complex, class I B (HLA-B) and C
(HLA-C), E
(HLA-E), G
(HLA-G). KIR3DL1 is activated
by HLA-B; NKG2A - by
HLA-E; KIR2DL1,
KIR2DL2; KIR2DL3 - by
HLA-C; KIR2DL4 - by
HLA-G. The ligand for KIR2DL5
is not known [1], [3], [18].
Inhibitory receptors block signals from the activating receptors by attraction of
phosphatase and following dephosphorylation of signaling proteins downstream of
activating receptors. Tow phosphatases: Tyrosine phosphatase protein tyrosine
phosphatase, non-receptor type 6
(SHP-1) and 11
(SHP-2) bind to inhibitory receptors upon ligand
recognition, [18], [20], [21]. Some receptors
recruits only one of two phosphatases, for example, KIR2DL4
requires SHP-2 [18]. The others receptors bind
both phosphatases, for example, KIR2DL2 [22].
Dephosphorylation by SHP-1 blocks association of the
adaptor protein LAT 1 with PLC-gamma
1 and PLC-gamma 2 {PMID:
8976179}, [23]. In addition, SHP-1
may inhibit Syk [24]. Both
SHP-1 and SHP-1
inhibit Lck [25], [26], [27].
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